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New Genetic Quirks Linked to Schizophrenia

Three new studies by international research teams provide the most complete picture to date of the genetic glitches that may contribute to schizophrenia. The studies confirm what recent smaller studies have hinted: that rare and diverse variations, at multiple locations in a person’s genome, raise the risk of schizophrenia.

Schizophrenia is a lifelong, disabling brain disorder that affects about 1 in 100 adults nationwide. The disease usually emerges in late adolescence or early adulthood, causing delusions, hallucinations and problems with thinking and concentration. Researchers believe that a complex set of genetic and environmental factors combine to cause schizophrenia, although the details remain unclear.

Working independently, 3 scientific teams—supported in part by NIH’s National Institute of Mental Health (NIMH)—conducted genome-wide association studies to find genetic factors linked to schizophrenia. Two of the studies looked for relatively large deletions or duplications—called structural variations—in the chromosomes of thousands of patients with schizophrenia. The third study looked at tiny variations called single nucleotide polymorphisms (SNPs) in strands of DNA.

The 2 larger studies—published in the July 30, 2008, online edition of Nature—both implicated 2 previously unknown, rare deletions on chromosomes 1 and 15 as risk factors for schizophrenia. Both also confirmed the involvement of a previously identified deletion on chromosome 22. One of the studies, which compared the genomes of nearly 5,000 patients with schizophrenia to more than 41,000 controls, revealed that a second new deletion on chromosome 15 is significantly associated with schizophrenia.

The second large study scanned the genomes of over 3,000 patients with schizophrenia and about 3,000 controls. The researchers found a greater overall frequency of rare structural variations—both duplications and deletions—in those with schizophrenia. Scientists do not yet understand exactly how these increased variations might translate into schizophrenia. “This surprising excess of many types of chromosomal changes in schizophrenia patients provides us with rich clues to follow up in future research,” says coauthor Dr. Pamela Sklar of Massachusetts General Hospital and the Broad Institute.

The third study, published online in Nature Genetics on July 30, 2008, identified at least 3 smaller genetic variants, or SNPs, as independent risk factors for schizophrenia. The research team, which included 2 NIMH scientists, scanned the genomes of nearly 500 people with schizophrenia and about 3,000 healthy controls. The strongest link to the disorder was seen in a SNP near the gene ZNF804A. This gene encodes a protein that may regulate the expression of other genes. The association with ZNF804A strengthened when patients with bipolar disorder were included in the analysis. This finding supports the notion that schizophrenia and bipolar disorder share some common risk factors.

Together, the 3 studies open up new avenues for future research. “We’re moving toward an understanding of the causes of the disease, but we’ve only explained a tiny fraction of why people might develop schizophrenia,” Sklar says. “Much more work needs to be done to connect the specific genetic changes to the full spectrum of the disorder, and to the ways they might interact with the environment.”